title: Combining in silico and biophysical methods for the development of Pseudomonas aeruginosa quorum sensing inhibitors: an alternative approach for structure-based drug design.
abstract: The present work deals with the optimization of an inhibitor of PqsD, an enzyme essential for Pseudomonas aeruginosa quorum sensing apparatus. Molecular docking studies, supported by biophysical methods (surface plasmon resonance, isothermal titration calorimetry, saturation transfer difference NMR), were used to illuminate the binding mode of the 5-aryl-ureidothiophene-2-carboxylic acids. Enabled to make profound predictions, structure-based optimization led to increased inhibitory potency. Finally a covalent inhibitor was obtained. Binding to the active site was confirmed by LC-ESI-MS and MALDI-TOF-MS experiments. Following this rational approach, potent PqsD inhibitors were efficiently developed within a short period of time. This example shows that a combination and careful application of in silico and biophysical methods represents a powerful complement to cocrystallography.
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization & Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: J Henning
authors.initials: JH
authors.lastname: Sahner
authors.forename: Christian
authors.initials: C
authors.lastname: Brengel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Storz
authors.forename: Matthias
authors.initials: M
authors.lastname: Groh
authors.forename: Alberto
authors.initials: A
authors.lastname: Plaza
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology; D053038:Quorum Sensing / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002264:Carboxylic Acids; D013876:Thiophenes